Phosphonate esters of alkyl acetoacetates



United States Patent 3,450,801 PHOSPHONATE ESTERS 0F ALKYL ACETOACETATES Thomas P. Dawson, Bel Air, and Charles E. Williamson,

Edgewood, Md., assignors to the United States of America as represented by the Secretary of the Army No Drawing. Continuation-impart of application Ser. No. 564,585, Feb. 9, 1965 This application Apr. 26, 195 7, Ser. No. 655,449

Int. Cl. C07f 9/40 U.S. Cl. 260-941 23 Claims This application is a continuation-in-part of application Ser. No. 564,585 filed Feb. 9, 1956, now abandoned.

The invention described herein may be manufactured and used by or for the Government of the United States of America for governmental purposes without the payment to us of any royalty thereon.

The invention relates to phosphonate esters of alkyl acetoacetates, particularly, 2 alkoxycarbonyl 1 methylvinyl alkyl alkylphosphonates.

In more detail the new compounds may be represented by the following general formula where R is an alkyl group containing not more than 3 carbon atoms, R is an open chain alkyl group containing not more than 8 carbon atoms, a cyclohexyl group, or an alkyl substituted cyclohexyl group containing not more than 16 carbon atoms, and R is an alkyl group containing not more than three carbon atoms. These compounds have an extremely high toxicity and anticholinesterase activity which makes them useful as chemical warfare agents. Those compounds in which R is methyl and R is cyclohexyl or alkyl substituted cyclohexyl are particularly toxic.

The compounds disclosed herein may be used in any type of munition suitable for disseminating relatively non-volatile agents, such as bombs, shells, spray tanks, aerosol generators, etc. They have very low vapor pressures.-

The present invention also includes a process of manufacturing 2-alkoxycarbonyl-l-methylvinyl alkyl alkylphosphonates wherein an alkali metal derivative of the acetoacetate,

is reacted with an alkyl or cycloalkyl alkylphosphonohalidate In these formulae M represents an alkali metal, preferably sodium or potassium, while X represents a halogen, preferably chlorine. R, R and R have the same signife icance as in the general formula, above.

Instead of using the sodium salt, the alkyl alkylphosphonohalidate may be reacted with the acetoacetic ester in the presence of an amine type HCl acceptor, preferably triethylamine, employing about one mole of the amine for each mole of the ester. In addition to triethylene, other trialkylamines, e.g., tributylamine, as well as cyclic amines, such as pyridine, diethylaniline and other tertiary amines may be used.

Our compounds exhibit cis-trans isomerism as follows:

One of the isomers has been found to possess percutaneous and intravenous toxicities considerably higher than the other. In the case of our preferred compounds the intravenous toxicity of the more toxic form was found to be more than ten times that of the less toxic form.

On the basis of the investigations which we have made, we believe that the more toxic isomer has the trans configuration and the less toxic the cis form. For purposes of this specification we therefore designate as the cis and trans isomers the less and more toxic isomers respectively, which are further characterized by the methods of preparation.

The reaction conditions determine which isomer pre dominates in the product, the trans form being favored by the use of the sodium salt and higher temperatures, while the cis form is favored by the use of amine and lower temperatures.

In some cases the amine process may be found to be more desirable from the standpoint of yield. The cis form produced may be converted to the trans form by several methods, all of which involve heating the cis material. Heating the cis form with tributylamine or the sodium salt of an alkyl acetoacetate gives approximately 90% conversion to the transform. Similar results have been obtained by storage for long periods of time at C. One of the best methods thus far found involves heating the cis form, in the presence of 4% of the sodium salt of methyl or ethyl acetoacetate, to 100 C. for one hour.

' This procedure not only gives a 90 conversion to the trans form but also removes a considerable proportion of certain impurities formed as a result of side reactions. When the amine process is used, the reaction is carried on in solution in a hydrocarbon, such as benzene, xylene, or petroleum distillates. When the salts are used, they may be suspended in hydrocarbons or dissolved in an anhydrous alcohol.

When employing the salt process, the preferred reactants are, as the acetoacetate, the sodium salts of ethyl acetoacetate, and methyl aeetoacetate.

and as the phosphonochloridate, cyclohexyl methylphosphonochloridate 3 and 3-methylcyclohexyl methylphosphonochloridate Ha Ha /CC\ CH3 H2O gP- 0 \CO All I Hz 11 CH3 Examples 1 and 2 show the preparation of two of our preferred compounds by the salt process.

EXAMPLE 1 Z-ethoxycarbonyl-l-methylvinyl cyclohexyl methylphosphonate A xylene suspension of the sodium salt of ethyl acetoacetate was prepared by adding ethyl acetoacetate (32.5 g., 0.25 M) to a solution of sodium ethoxide, made by dissolving metallic sodium (5.75 g., 0.25 M) in absolute ethanol (200 ml.). Cyclohexyl methylphosphonochloridate (49.5 g., 0.25 M) was added over a period of minutes while stirring and cooling. The reaction temperature was maintained at 80 C., and the mixture allowed to stir for an additional hour at 80 C. The solvent was then distilled off at reduced pressure and the residual oil dissolved in xylene (100 ml.). It was then washed with 5% sodium hydroxide solution (5x100 ml.), and water (5x100 ml.). After removal of the solvent at reduced pressure the product was evacuated to 2 mm. Hg at 50 C. for 2 hours. The unvaporized material constitutes the product. The yield was 35.6 g. (=49.1%

EXAMPLE 2 2-ethoxycarbonyl-l-methylvinyl 3-methylcyclohexyl methylphosphonate A xylene suspension of the sodium salt of ethyl acetoacetate was prepared by adding sodium metal (11.5 g., 0.5 M) to a xylene solution of ethyl acetoacetate, made by dissolving ethyl acetoacetate (65.07 g., 0.5 M) in dry xylene (500 ml.). 3-methylcyclohexyl methylphosphonochloridate (0.5 M) was added slowly while stirring and cooling. The reaction temperature was maintained at 80 C., and the mixture allowed to stir for an additional hour at 80 C. It was then washed with 5% sodium hydroxide solution (8 X 125 ml.), and water (8 x125 ml.) After removal of the solvent at reduced pressure the product was evacuated to 1 mm. Hg at 60 C. for 3 hours. The yield was 52 g. (=34%), based on methylphosphonic dichloride.

The following examples show the production of two of our preferred compounds by the amine process.

EXAMPLE 3 2-methoxycar-bonyl-1-methylvinyl cyclohexyl methylphosphonate (trans form) Methylphosphonic dichloride (33.2 g., 0.25 M) and triethylamine (25 g., 0.25 M) were dissolved in 200 ml. of benzene and cyclohexanol (25 g., 0.25 M) was added slowly while stirring and cooling. The reaction temperature was maintained at 1015 C. After stirring at room temperature for 2 hours, triethylamine (25 g., 0.25 M) was added and then methyl acetoacetate (29 g., 0.25 M) was added slowly while stirring and cooling. The reaction temperature was maintained at 20 C. After stirring for an additional 2 hours at room temperature and standing overnight the mixture was washed with 5% NaOH solution (4x100 ml.) and then water (4x100 ml.). The solvent was then removed by distillation at reduced pressure and 4% of the sodium salt of methyl acetoacetate was added. The mixture was heated to 100 C. for one hour and then rewashed with 5% NaOH solution (4X 100 ml.) and water (4x100 ml.) in benzene solution. The solvent was then removed by distillation at reduced pressure and the residue molecularly distilled at 80 C. at 10* mm. Hg. A yield of 30.1 g. (=43.6%) was obtained. This material was then crystallized by cooling to yield colorless needless melting at 43 C.

Analysis.Calculated for C H O P: C, 52.17; H, 7.66; P, 11.21. Found: C, 52.2; H, 7.86; P, 11.2.

EXAMPLE 4 2-ethoxycarbonyl-l-methylvinyl 3-methylcyclohexyl methylphosphonate (cis isomer) Methylphosphonic dichloride (132.9 g., 1.0 M) and triethylamine (101 g., 1.0 M) were dissolved in 1 l. of benzene contained in a 3 1. reaction flask equipped with an outlet at the bottom of the flask. 3-methylcyclohexanol (114.2 g., 1.0 M) was added slowly while stirring and cooling. The reaction temperature was maintained at 35 C. After stirring for an additional 30 minutes, triethylamine 101 g., 1.0 M) was added and then ethyl acetoacetate (130.1 g., 1.0 M) was added slowly while stirring and cooling. The reaction temperature was maintained at 35 C. After stirring for an additional 30 minutes the reaction mixture was washed with 5% NaOH solution (3x150 ml.) followed by water (3x100 ml.). The benzene solution containing the isomer was then removed from the reaction flask and the solvent was removed by distillation at reduced pressure. A yield of 238.7 g. (=78.4%) was obtained.

AnaIysis.-Calculated for C H O P: C, 55.25; H, 8.28; P, 10.18. Found: C, 55.9; H, 8.3; P, 10.1.

The infrared spectrum of this material showed it to be approximately cis. It can be converted to the trans isomer by heating with the sodium salt of ethyl acetoacetate or by the other methods described above.

By following the methods given above, the other compounds of our genus may be produced by simply substituting the proper acetoacetic ester or salt thereof and the proper phosphonohalidate. For example, the trans isomer of 2-methoxycarbonyl-l-methylvinyl 3-methylcyclohexyl methylphosphonate may be made by the process of Example 2, substituting 0.5 M of methyl acetoacetate for the ethyl acetoacetate, or by the process of Example 3, substituting 0.25 M of 3-methylcyclohexanol for the cyclohexanol of that example. The following examples show further compounds which are somewhat less toxic than our preferred examples given above.

EXAMPLE 5 2-ethoxycarbonyl-1-methylvinyl 3,3,5-trimethylcyclohexyl methylphosphonate Ethyl acetoacetate (97.6 g., 0.75 mole) was dissolved in 500 ml. of xylene and sodium metal (11.5 g., 0.5 mole) was added. The mixture was stirred and heated to until the sodium salt had completely formed. It was then cooled to 25 and 3,3,5-trimethylcyclohexyl methylphosphonochloridate (119.3 g., 0.5 mole) which had been prepared from the low-melting isomer of 3,3,5-trimethylcyclohexanol, was added slowly while the mixture was stirred and cooled to 20-25. After standing overnight, the mixture was washed with 5% NaOH solution (8x125 ml.), followed by an equal amount of water. The solvent was stripped off at reduced pressure leaving a crude yield of 128 g. (77% This material was then distilled at .05 mm.

Analysis.Calcd. for C H O P: P, 9.3. Found: P, 9.2.

EXAMPLE 6 Z-ethoxycarbonyl-l-methylvinyl methyl methylphosphonate Equimolar quantities of methyl methylphosphonochloridate and triethylamine are dissolved in benzene. Ethyl acetoacetate is then added in equimolar proportions with constant stirring. During the addition the reaction mixture is maintained at a temperature of about 25 C. by cooling. It is then stirred for an additional two hours at room temperature. The product is then recovered and the compounds converted to the trans form in the manner described in Example 3.

EXAMPLE 7 2-ethoxycarbonyl-l-methylvinyl isopropyl methylphosphonate Equimolar quantities of isopropyl methylphosphonochloridate and triethylamine are dissolved in xylene. Equimolar quantities of ethyl acetoacetate are added with constant stirring and cooling, the temperature being maintained at about 25 C. The mixture is then stirred for about two hours at room temperature and the product is recovered and converted to the trans form in the same manner as given in Example 3.

EXAMPLE 8 2-ethoxycarbonyl-l-methylvinyl n-octyl methylphosphonate Methylphosphonic dichloride and triethylamine, in equimolar proportions, are dissolved in xylene. A xylene solution of n-octyl alcohol is then added slowly with constant stirring and cooling, the temperature being maintained at ll5 C. The reaction mixture is allowed to warm to room temperature and finally heated to 40-45 C. for two hours. The solution now contains n-octyl methylphosphonochloridate. An equimolar quantity of triethylamine is again added and ethylacetoacetate is added slowly with stirring and cooling, the temperature being maintained as in the other examples at about C. After stirring for an additional hour, the product is recovered and converted to the trans form in the same manner as in Example 3.

EXAMPLE 9 Z-ethoxycarbouyl-l-methylvinyl diisopropylcarbinyl methyl phosphonate Diisopropylcarbinyl methylphosphonochloridate is prepared by reacting diisopropylcarbinol with methylphosphonodichloride in the presence of triethylamine in xylene solution, to form diisopropylcarbinyl methylphosphonochloridate, the same procedure being used as given in Example 8. An equimolar amount of diethylamine is then dissolved in the solution and an equimolar amount of ethyl acetoacetate is added slowly with cooling to about 25 C. After stirring for another hour at room temperature, the produce is recovered and converted to the trans isomer in the manner described in Example 3.

EXAMPLE l0 2-ethoxycarbonyl-1-methylvinyl 2-methylcyclohexyl methylphosphonate Z-methylcyclohexyl methylphosphonochloridate and triethylamine are dissolved in equimolar proportions in benzene. An equimolar quantity of ethylacetoacetate is then added slowly with constant stirring and cooling, the tem perature being maintained at about 25 C. After stirring for another hour, the product is separated and converted to the trans form in the manner described in Example 3.

EXAMPLE 1 1 2-ethoxycarbonyl-l-methylvinyl 4-cyclohexylcyclohexyl methylphosphonate 4-cyclohexylcyclohexyl methylphosphonochloridate and triethylamine are dissolved in benzene in equimolar proportions. An equimolar amount of ethyl acetoacetate is then added slowly with constant stirring and cooling, the temperature being maintained at about 25 C. It is stirred for another hour at room temperature. The product is then recovered and converted to the trans form by the method described in Example 3.

6 EXAMPLE 12 Z-methoxycarbonyl-l-methylvinyl cyclohexyl ethylphosphonate Ethylphosphonic dichloride is dissolved in xylene together with an equimolar quantity of triethylamine. An equimolar amount of cyclohexanol is then added slowly with stirring and cooling, the temperature being maintained at about 25 C. Stirring is then continued at room temperature for an additional hour. An equimolar quantity of triethylamine is again added and methyl acetoacetate is then introduced slowly with constant stirring and cooling to about 25 C., and the mixture is stirred for an additional hour at room temperature. The product is separated and converted to the trans form in the same manner as in Example 3.

EXAMPLE 13 2-isopropoxycarbonyl-1-methylvinyl cyclohexyl methylphosphonate' Cyclohexyl methylphosphonochloridate is dissolved in xylene together with an equimolar quantity of triethylamine. An equimolar quantity of isopropyl acetoacetate is then added slowly with stirring. The temperature is maintained at about 25 C. by cooling. After stirring for an additional hour at room temperature the product i recovered and converted to the trans form in the same manner as described in Example 3.

EXAMPLE 14 2-isopropoxycarbonyl-l-methylvinyl cyclohexyl isopropylphosphonate Isopropylphosphonic dichloride and triethylamine are dissolved in benzene in equimolar proportions. An equimolar quantity of cyclohexanol is then added slowly with agitation and cooling. The temperature is maintained at about 25 C. The mixture is then stirred for an additional hour at room temperature. An equimolar quantity of isopropyl acetoacetate is then added with cooling to 25 C. and stirring. The mixture is then stirred for an additional two hours at room temperature. The product is recovered and converted to the trans form in the manner described in Example 3.

EXAMPLE 15 2-isopropoxycarbonyl-l-methylvinyl 3-methylcyclohexyl isopropylphosphonate Isopropylphosphonic dichloride is dissolved in benzene and an equimolar quantity of triethylamine is added. 3- methylcyclohexanol is added slowly, 'with cooling, in equimolar proportions. The mixture is then stirred for an additional hour at room temperature. An equimolar quantity of triethylamine is then added, and isopropyl acetoacetate is introduced slowly with cooling. The temperature is maintained at about 25 C. The mixture is stirred for an additional hour at room temperature and the product is recovered and converted to the trans form in the manner described in Example 3.

It will be realized that the above examples are not exhaustive, but are merely exemplary of the compounds that may be produced by our process. It will also be understood that various modifications may be made in the details of the process as disclosed. We therefore wish our invention to be limited solely by the scope of the appended claims.

'We claim: 1. A compound having the formula 0 1 ll RPOC=CHCOR3 OR2 CH3 wherein R is an open chain alkyl radical containing not more than 3 carbon atoms, R is selected from the group consisting of open chain alkyl radicals containing not more than 8 carbon atoms, the cyclohexyl radical, and

alkyl-substituted cyclohexyl radicals containing not more than 16 carbon atoms, and R is an alkyl radical containing not more than three carbon atoms.

2. 2-ethoxycarbonyl-l-methylvinyl cyclohexyl methylphosphonate.

3. 2-ethoxycarbonyl-l-methylvinyl 3-methylcyclohexyl methylphosphonate.

4. Z-ethoxycarbonyl 1 methylvinyl 3,3,5-trimethylcyclohexyl methylphosphonate.

5. 2-methoxycarbonyl-l-methylvinylcyclohexyl methylphosphonate.

6. Z-methoxycarbonyl 1 methylvinyl 3-methylcyclohexyl methylphosphonate.

7. 2-ethoxycarbonyl 1 methylvinyl methyl methylphosphonate.

8. The trans isomer of a compound as defined in claim 1.

9. The trans isomer of the compound defined in claim 2.

10. The trans isomer of the compound defined in claim 3.

11. The claim 4.

12. The claim 5.

13. The claim 6.

14. The claim 7.

15. A process of preparing a compound of the formula trans isomer of the compound defined in trans isomer of the compound defined in trans isomer of the compound defined in trans isomer of the compound defined in R'-i o-o=oH- i-om R2 H3 which comprises mixing an alkylphosphonochloridate of the formula 0 Ira-$01 in an inert solvent with a compound selected from the group consisting of alkyl acetoacetates of the formula 12 -o-ii-om-ii-cm and their alkali metal derivatives of the formula R in the above formulas being an alkyl group containing not more than three carbon atoms, R being selected from the class consisting of alkyl groups containing not more than eight carbon atoms, the cyclohexyl group, and alkylsubstituted cyclohexyl groups containing not more than sixteen carbon atoms, R being an alkyl group containing not more than three carbon atoms, and M being selected from the class consisting of sodium and potassium.

16. A process as defined in claim .15 wherein the said alkyl phosphonochloridate is reacted with the said alkali metal derivative in an inert solvent at a temperature of about C.

17. A process as defined in claim 15 wherein the said phosphonochloridate is reacted with said alkyl acetoacetate in an inert solvent in the presence of an amine at a temperature of about 25 C.

18. A process as defined in claim 17 wherein said amine is triethyla-mine.

19. A process as defined in claim 17 which further comprises heating the reaction product to a temperature of about C. in the presence of a sodium salt of an alkyl acetoacetate.

20. The process of converting a compound as defined in claim 1 from the cis to the trans form which comprises heating said compound to a temperature of at least 50 C.

21. A process as defined in claim 20 which comprises storing said phosphonate for an extended period of time at a temperature of about 50 C.

22. A process as defined in claim 20 which comprises heating said phosphonate at a temperature of about 100 C. in the presence of a compound selected from the group consisting of lower alkyl tertiary amines and alkali metal salts of alkyl acetoacetates.

23. A process as defined in claim 20 which comprises heating said phosphonate in the presence of the sodium salt of the corresponding 'acetoacetate for about four hours at a temperature of about 100 C.

References Cited UNITED STATES PATENTS 2,685,552 8/1954 Stiles 4242 l2 LELAND A. SEBASTIAN, Primary Examiner.

US. Cl. XJR. 

1. A COMPOUND HAVING THE FORMULA
 15. A PROCESS OF PREPARING A COMPOUND OF THE FORMULA 